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Authors: Fu-Shun Yen, Teng-Shun Yu, Chih-Cheng Hsu, Chii-Min Hwu
Journal: Clinical Gastroenterology and Hepatology (2023)

We greatly appreciate the comments1Yuanyuan L. et al.Clin Gastroenterol Hepatol. 2024; 22: 1142-1143Google Scholar by Yuanyuan Li and Xiaoze Wang on our paper "Glucagon-like peptide-1 receptor agonist use in patients with liver cirrhosis and type 2 diabetes."2Yen F.S. et al.Clin Gastroenterol Hepatol. Published online June. 2023; 16https://doi.org/10.1016/j.cgh.2023.06.004Abstract Full Text Full Text PDF Scopus (10) Google Scholar It looks interesting and practical to compare similarity and difference of disease progress between the Simon's study3Simon T.G. et al.Clin Gastroenterol Hepatol. 2022; 20: 1382-1393Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar (cirrhosis mainly caused by nonalcoholic fatty liver disease) and ours (cirrhosis mainly caused by hepatitis B or C virus infection). The authors expressed concerns about the nonsignificant difference in the risk of decompensated cirrhosis and hepatic encephalopathy between glucagon-like peptide-1 receptor agonist (GLP-1 RA) users and nonusers after using competing risk analysis with death as the competing risk in our study. We acknowledge these concerns. However, we believe that the lack of statistical significance may be caused by the small number of patients (467) after propensity score matching, resulting in fewer cases of decompensated cirrhosis and hepatic encephalopathy. Instead of propensity score matching, we used the inverse probability of treatment weighting as a covariate adjusted in the regression models to preserve sample size; then, using death as a competing risk, we performed competing risk-adjusted analyses in risk assessment of decompensated cirrhosis and hepatic encephalopathy between GLP-1 RA users and nonusers. The new results showed GLP-1 RA users had a significantly lower risk of decompensated cirrhosis (adjusted hazard ratio [aHR], 0.74; 95% confidence interval [CI], 0.58–0.96; P = .021), and hepatic encephalopathy (aHR, 0.67; 95% CI, 0.46–0.98; P = .038) than nonusers (Supplementary Table 1). We also used inverse probability of treatment weighting adjustment to compare the risk of liver-related death (death from cirrhosis, decompensated cirrhosis, liver failure, and hepatocellular carcinoma confirmed by the National Death Registry) between GLP-1 RA users and nonusers in patients with compensated cirrhosis. The number and incidence rates of liver-related deaths between GLP-1 RA users and nonusers were (19 and 2011) and (11.62 and 12.71 per 1000 person-years), respectively. GLP-1 RA users were associated with a nonsignificantly lower risk of liver-related death (aHR, 0.82; 95% CI, 0.51–1.29; P = .386) than nonusers. In addition to small sample size and short follow-up time, possible inaccuracies in recording causes of death for our study subjects, such as misclassifying death because of end-stage cirrhosis, liver failure, liver cancer–related weakness, shock from variceal bleeding, and hepatic coma as death of cardiopulmonary failure, may also lead to underrepresentation of liver-related deaths, resulting in inadequate statistical power and nonsignificant results. Our study aligned with others may not be able to ascertain the actual cause of death protected by GLP-1 RA use.4Mokdad A.A. et al.BMC Med. 2014; 12: 145Crossref PubMed Scopus (777) Google Scholar In our study group, 84% of patients with cirrhosis were treated with insulin. We believe this may be because until 2019, diabetes treatment guidelines focused primarily on glycemic control. Only recently have guidelines focused on organ protection begun to emerge.5American Diabetes AssociationClin Diabetes. 2019; 37: 11-34Crossref PubMed Scopus (362) Google Scholar In addition, under our national health insurance regulations, GLP-1 RA could only be prescribed after the maximum dose of other antidiabetic medications had been used for 6 months and hemoglobin A1C remained greater than 8.5%. As a result, most physicians in Taiwan prescribe GLP-1 RA when insulin or insulin secretagogues fail to adequately lower blood glucose levels. Our study spans from 2008 to 2019, in which the treatment guideline focused on glycemic control; in accordance with the National Health Insurance Administration regulations, many GLP-1 RA users also used insulin. Another study from Taiwan showed that 77.9% of patients with diabetes without cardiovascular disease treated with GLP-1 RA were also using insulin.6Yang Y.S. et al.Diabetes Care. 2022; 45: 1184-1192Crossref PubMed Scopus (8) Google Scholar Thus, it seems that nearly 80% of patients on GLP-1 RA in Taiwan are on insulin therapy, which may be a common trend in this country during the study period and not an indication that we have selected a group of patients with severe disease. In conclusion, the use of GLP-1 RA in patients with cirrhosis caused by nonalcoholic fatty liver disease or viral hepatitis may reduce the risk of decompensated cirrhosis and hepatic encephalopathy. It may also reduce the risk of mortality in these patients. However, the exact cause of the observed protective effect against death is not certain. A larger study population, longer follow-up, and more definitive cause of death data may be needed to clarify this issue. Supplementary Table 1HRs and CIs for Outcomes Among the Sampled Patients (Crude and After IPTW Adjustment)OutcomeCoexisting T2D and cirrhosis without GLP-1 RAsCoexisting T2D and cirrhosis with GLP-1 RAscHR95% CIP valueaHRaAdjusted by IPTW, and sex, age, comorbidities medication, Charlson Comorbidity Index, Diabetes Complication Severity Index, and duration of T2D, as shown in Table 1.295% CIP valuenPYIRnPYIRMACE462814,937830.98208674,84827.860.970.73–1.29.84110.670.5–0.9.0081Decompensated cirrhosis688114,503647.44311672,87642.760.730.56–0.94.0160.630.49–0.83< .001Decompensated cirrhosisbTaking death as a competing risk for subdistribution competing risk analysis of nondeath outcomes.0.740.58–0.96.0210.740.58–0.96.021 Variceal bleeding104515,75406.6316877,7842.160.430.18–1.04.06130.370.15–0.9.0287 Ascites393815,197125.92159276,55720.800.840.61–1.16.28050.690.5–0.96.0269 Hepatic encephalopathy373715,394324.28196374,46026.360.70.49–1.02.06440.620.42–0.9.0128 Hepatic encephalopathybTaking death as a competing risk for subdistribution competing risk analysis of nondeath outcomes.0.730.05–1.05.08760.670.46–0.98.0384Liver failure425915,294727.85206474,16027.830.680.48–0.97.03220.60.42–0.86.0058Hepatocellular carcinoma434815,313628.39166876,26521.870.980.72–1.34.92260.990.72–1.35.9319Liver-related deaths201115,825612.7119163511.620.980.62–1.54.93040.820.51–1.29.3861All-cause deaths840316,014052.47254078,21232.480.560.41–0.75< .0010.460.34–0.62< .001aHR, adjusted hazard ratio; cHR, crude hazard ratio; CI, confidence interval; GLP-1 RA, glucagon-like peptide-1 receptor agonists; IPTW, inverse probability of treatment weighting; IR, incidence rate (per 1000 person-years); MACE, major adverse cardiovascular events; PY, person-years; T2D, type 2 diabetes.a Adjusted by IPTW, and sex, age, comorbidities medication, Charlson Comorbidity Index, Diabetes Complication Severity Index, and duration of T2D, as shown in Table 1.2Yen F.S. et al.Clin Gastroenterol Hepatol. Published online June. 2023; 16https://doi.org/10.1016/j.cgh.2023.06.004Abstract Full Text Full Text PDF Scopus (10) Google Scholarb Taking death as a competing risk for subdistribution competing risk analysis of nondeath outcomes. Open table in a new tab aHR, adjusted hazard ratio; cHR, crude hazard ratio; CI, confidence interval; GLP-1 RA, glucagon-like peptide-1 receptor agonists; IPTW, inverse probability of treatment weighting; IR, incidence rate (per 1000 person-years); MACE, major adverse cardiovascular events; PY, person-years; T2D, type 2 diabetes. Glucagon-Like Peptide-1 Receptor Agonists: Best Choice for Patients With Cirrhosis and Diabetes?Clinical Gastroenterology and HepatologyVol. 22Issue 5PreviewWe read with interest the recently published original article by Yen et al1 on the long-term outcomes of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes and cirrhosis. This national population-based study used a comparative effectiveness research methodology using administrative databases and presented reliable data to inform patient care decisions. The findings indicate that the utilization of GLP-1 RAs is linked to reduced incidences of cirrhotic decompensation, liver failure, cardiovascular events, and all-cause mortality among individuals diagnosed with type 2 diabetes and compensated liver cirrhosis. Full-Text PDF